Igor Puzanov1, Antoni Ribas2, Caroline Robert3, Jacob Schachter4, Marta Nyakas5, Adil Daud6, Ana Arance7, Matteo S Carlino8,9, Steven J O'Day10, Georgina V Long9,11, Kim A Margolin12, Reinhard Dummer13, Dirk Schadendorf14, Jose Lutzky15, Paolo A Ascierto16, Ahmad Tarhini17, Jianxin Lin18, Robin Mogg19, Blanca Homet Moreno18, Nageatte Ibrahim18, Omid Hamid20. 1. Roswell Park Cancer Institute, Buffalo, New York. 2. University of California, Los Angeles. 3. Gustave Roussy, Paris-Sud University, Villejuif, France. 4. The Chaim Sheba Medical Center at Tel Hashomer, Ramat Gan, Israel. 5. Department of Oncology, Oslo University Hospital-Radiumhospitalet, Oslo, Norway. 6. Department of Medicine, University of California, San Francisco. 7. Hospital Clinic de Barcelona, Barcelona, Spain. 8. Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia. 9. Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. 10. John Wayne Cancer Institute, Providence St John's Health Center, Santa Monica, California. 11. Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. 12. City of Hope National Medical Center, Duarte, California. 13. University Hospital of Zürich, Zürich, Switzerland. 14. University Hospital Essen, Essen, Germany. 15. Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. 16. Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. 17. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 18. Merck & Co, Inc, Kenilworth, New Jersey. 19. The Bill and Melinda Gates Medical Research Institute, Cambridge, Massachusetts. 20. The Angeles Clinic and Research Institute, Los Angeles, California.
Abstract
Importance: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established. Objective: To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab. Design, Setting, and Participants: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had receivedpembrolizumab. Interventions: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. Main Outcomes and Measures: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy. Results: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively. Conclusions and Relevance: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.
RCT Entities:
Importance: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAFV600E/K-mutant melanoma is not well established. Objective: To assess the association of BRAF wild-type (WT) or BRAFV600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab. Design, Setting, and Participants: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAFV600E/Ktumor status who had received pembrolizumab. Interventions: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. Main Outcomes and Measures: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAFV600E/K-mutant melanoma and BRAFV600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy. Results: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAFV600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAFV600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively. Conclusions and Relevance: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAFV600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.
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